7. Project Summary Experiments proposed in this project will examine cognitive dysfunction and underlying neurochemical changes caused by co-use of alcohol and cannabis during adolescence. Cognitive impairments including loss of memory function and impulse control, and poor decision making often occur in chronic drug users. Such cognitive dysfunction contributes to the persistence of drug addiction and poor addiction treatment outcomes. Chronic use of alcohol or cannabis is associated with deficits in learning and memory, attention, and executive function. The same drugs also produce anatomical abnormalities in the prefrontal cortex (PFC) and hippocampus (HP) in both humans and rodents. Furthermore, recent human studies indicate that co-use of alcohol and cannabis leads to worse health outcomes compared to the use of either drug alone. The underlying neurobiological mechanisms of the more detrimental effects of alcohol and THC co-use are unknown. Alcohol interacts with multiple neurotransmitter systems including the endocannabinoid system, which is the main neural substrate that mediates the psychoactive effects of cannabis. Reports from previous studies have provided evidence that repeated exposure to either alcohol or ?9-tetrahydrocannibinol (THC), the main psychoactive constituent of cannabis, can lead to dysregulation of the endocannabinoid system. Importantly, recent data have revealed that deficiency of the endocannabinoid system increases the risk of developing cognitive dysfunction. Thus, the main hypothesis of this proposal is that co-use of alcohol and THC compromises the endocannabinoid system to a greater extent than the use of either drug alone and, in doing so, causes worst cognitive impairments. Because co-use of the two drugs occurs most frequently during adolescence, which is a critical period for the maturation of neural control on cognition, drug taking in adolescent rats will be used as a model to test the hypothesis. Aim 1 will assess learning and memory and behavioral flexibility with a Barnes maze and a novel object recognition task after repeated voluntary eating of THC-infused cookies, alcohol drinking, or the joint consumption of both drugs during adolescence in male and female rats. Aim 2 will examine expression of genes involved in the endocannabinoid system and measure levels of endocannabinoids in the PFC and HP from rats that completed behavioral tests during Aim 1. Results acquired from this one-year proposal will be the basis for developing a larger research program and subsequent application for further elucidation of how the endocannabinoid system in specific forebrain circuits alters cognitive function in drug addiction.